The intestinal epithelium is a complex membrane made up of distinct areas (villi and crypts) and different cell types, each capable of the bidirectional transport of electrolytes and water. Over the past 30 years, major attention has been directed at an understanding of intestinal absorption, but recent investigations of the pathophysiology of cholera has renewed interest in intestinal secretory mechanisms. The overall goal of this research is to explore intestinal water and electrolyte transport in an attempt to develop hypotheses which will explain intestinal secretion and which can be put to rigorous test. Mechanisms of transport will be studied at both organ and cellular levels using (1) normal intestine in which secretion of electrolytes and/or water occurs spontaneously or has been induced by pharmacological agents such as bacterial exotoxins, hormones or drugs; or (2) pathological intestine characterized by cryptal hyperplasia and villous atrophy in which secretion occurs. Major attention will be directed toward characterization of specific active ionic secretory mechanisms (pumps) with regard to their nature, location and neurohumoral control. The methods of study will be chiefly measurements of bidirectional ionic fluxes coupled with measurements of the transmural potential difference and short-circuit current to allow a thermodynamic definition of the transport mechanism. These studies should extend our knowledge of a long-ignored area of gastrointestinal physiology, and through a fundamental understanding of these secretory processes will hopefully lead to a better understanding of diarrheal disease and rational approaches to therapy. The level of original funding has proven to be insufficient to carry out these research goals. This supplementary application documents this, and requests the necessary funds to maintain the current research effort.